Alpha-(n-benzoyloxy and phenylamino alkyl-piperazino)-beta-benzoyl-propionic acid derivatives

ABSTRACT

The present invention relates to new pharmacologically valuable ketone derivatives exhibiting a distinct dilatory action on the cerebral vessels and which have the general formula   AND THEIR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS, WHEREIN R1 stands for a member selected from the group consisting of CN, -CONH2, -COOH, -COONa and -COOK, R2 stands for a member selected from the group consisting of   X stands for alkylene having 1 to 4 carbon atoms, Y stands for a member selected from the group consisting of -OCO- and -CO-NH-, R3 and R4 each stand for a member selected from the group consisting of hydrogen and alkyl having 1 to 6 carbon atoms, R5 stands for a member selected from the group consisting of hydrogen and -OH, the nucleus I may have 1 to 3 alkoxy, halogen, alkyl or nitro substituents, THE NUCLEUS II may have 1 to 3 alkoxy, halogen or alkyl substituents THE NUCLEUS III may be substituted by 1 to 3 methoxy groups and to processes for producing said ketone derivatives.

United States Patent [191 Raabe et al.

[451 Feb. 18,1975

[ ALPHA-(N-BENZOYLOXY AND Pl-IENYLAMINO ALKYL-PIPERAZINO)-BETA-BENZOYL-PROPIONIC ACID DERIVATIVES [75] lnventors: Thomas Raabe, Heusenstammuber Offenbach, Germany; Aldolf Stachel, deceased, late of Offenbach,Germany by Ingeburg Lydia Katharina Stachel, heiress; Josef Scholtholt,Frankfurt am (Main)-Fechenheim; Rolf-Eberhard Nitz, Bergen-Enkheim, bothof Germany [73] Assignee: Cassela Farbwerke Mainkur Aktiengesellschaft,Frankfurt (Main), Germany [22] Filed: May 11, 1973 [21] Appl. No.:359,440

Related US. Application Data [62] Division of Ser. No. 239,359, March29, 1972.

[52] US. Cl. 260/268 R, 260/268 CN, 260/465 K, 260/465 E, 260/518 R,260/518 A, 260/558 [51] Int. Cl C07d 51/70 [58] Field of Search 260/268R, 268 CN [56] References Cited UNITED STATES PATENTS 3,594,384 7/1971Stachel et al 260/268 CN Primary Examiner-Donald G. Daus AssistantExaminer-Jose Tovar Attorney, Agent, or Firm-Francis M. Crawford [57]ABSTRACT The present invention relates to new pharmacologically valuableketone derivatives exhibiting a distinct dilatory action on the cerebralvessels and which have the general formula and their pharmaceuticallyacceptable acid addition salts, wherein R stands for a member selectedfrom the group consisting of CN, CONH COOH, COONa and COOK,

R stands for a member selected from the group consisting of and groupsand to processes for producing said ketone derivatives.

5 Claims, No Drawings 1 ALPHA-(N-BENZOYLOXY AND PHENYLAMINOALKYL-PIPERAZINO)-BETA-BENZOYL- PROPIONIC ACID DERIVATIVES Thisapplication is a division of application Ser. No, 239,359, filed Mar.29, I972.

The present invention relates to new, pharmacologically valuable ketonederivatives of the general forwherein R, stands for CN, CONH COOH, COONaor COOK, R stands for X stands for alkylene having 1 to 4 carbon atoms,

Y stands for -O-CO or -CONH- R and R each stand for hydrogen or alkylhaving up to 6 carbon atoms, and

R stands for hydrogen or OH,

the nucleus I may have I to 3 alkoxy, halogen, alkyl or nitrosubstituents,

the nucleus Il may have i to 3 alkoxy, halogen or alkyl substituents,and

the nucleus III may be substituted by l to 3 methoxy groups,

The symbols R,, R R R R X and Y used in the above formula have the samemeanings throughout the specification, and nuclei indexed I, II or IIImay be substituted as defined above.

The compounds of general formula l contain at least one basic nitrogenatom and may consequently form or be formed as salts, in particularhydrohalides, and the invention extends to such acid addition salts,Where pharmaceutically acceptable.

Preferred halogen substituents for the nucleus I and /or the nucleus IIare fluorine, chlorine and bromine. Preferred alkyl substituents of thenuecleus I and of the nucleus [1 contain 1 to 8 carbon atoms. Preferredalkoxy substuents are methoxy groups.

The compounds of formula I may be prepared, for example, by the additionof amines of the general formula to compounds of the general formulaThose compounds of formula I in which R stands for and Y represents the-OCO group, so that they have the general formula may also besynthesized by the addition of amines hav- I ing the general formula tocompounds of the general formula III followed by esterifiction of theadduets with bcnzoic acid derivatives of the general formula wherein Zstands for a halogen atom or the radical Those compounds of formula I inwhich R stands for a nitrile group may also be prepared by addition ofHCN to vinylogous amines of the general formula COOII VII VIII

or, in some cases, by diazotation of the corresponding carbonamides Xaccording to the following reaction equation:

OOH

XI v

with trimethylamine and subsequent reaction with KCN:

V..- XIX...

The chlorides Xl necessary for this purpose may be prepared, as far asthey are not yet described in literature, according to known per semethods. The simplest method for the prepartion of the chlorides Xlconsists in the addition, in the presence of Friedel-Crafts-typecatalysts, of suitable acid chlorides XV on acetylene according to thefollowing reaction equation:

In the case of certain acid chlorides this reaction is difficult tocarry out, for instance if the nucleus 1 bears one or more alkoxygroups. In this case the corresponding acetophenones XVl are subjectedto an alkaline ester condensation with formiates. From the sodium orpotassium salts XVII of the benzoylvinylalcohols thus obtained it ispossible to prepare by way of hydrolysis the benzoylvinylalcohols XVIIIwhich on their part may be converted with suitable chlorinating agents,such as thionylchloride or phosphortrichloride, to thebenzoylvinylehlorides X1:

HCOOCzHs I C CH3 NaO CH3 XVI XVII

XVIII Initial compounds of formula lll wherein R represents the CONHgroup may be prepared by partial saponification of the correspondingnitriles, for in- 4 stance with concentrated sulfuric acid according tothe following reaction scheme:

Initial compounds of formula III wherein R represents the COOH group maybe prepared either by diazotation of the corresponding carbonamides XXaccording to the following reaction scheme or directly by saponificationofthe nitriles XIX according to the following scheme or by reaction ofmaleic acid anhydride with the corresponding benzene derivatives underthe conditions of the Freidel-Crafts reaction l O o The compounds ofgeneral formula l of the present invention are valuablepharamaceuticals. They exert, especially where R, means CN, forinstance, a distinct dilatory action on the cerebral vessels and are, inthis respect, far superior to other known substances of this kind. Thecompounds of the present invention and their pharmaceutically acceptablesalts may be employed together with pharmaceutically acceptable diluentsor carriers for the preparation of pharmaceutical formulations such astablets, dragees, suppositories, capsules, solutions, suspensions oremulsions.

These pharmaceutical preparations may also contain other therapeuticallyactive substances.

Pharmacological investigations of the dilatory action of compoundsaccording to the invention on the cerebral vessels were carried out inanaesthetized dogs by observing the changes in blood flow and oxygentension of the brain-surface. The dogs were anaesthetized withUrethane-Chloralose-Dial-Nembutal (250-1 5- 1 0-4 mg./kg. i.v.). Overthe left-hand hemisphere of the brain the skull and the dura mater wereopened by circular incision with a diameter of 2 to 3 cms. Aheatconductive probe (Standard model P l of Messrs. Hartmann and BraunA.G., Frankfurt/Main) was applied to the brain under a slight pressurefor local blood flow determinations in the cerebral cortex (Literatureconsuited: K. GOLENHOFFEN, H. HENSEL, G. HlLDE- BRANDT:Durchblutungsmessung mit Warmeleitelementen in Forschung und Klinik,Georg Thieme Verlag Stuttgart, I963). Besides the heat-conductive probe,a teflon-coated multiwire-platinum electrode The following table givesthe results of the above pharmacological investigations.

6 7 EXAMPLE 1 2.87 g. p-chlorobenzoylacrylonitrile (formula:

dioxane, 2.27 g. norephedrin are added, the reaction mixture iscompletely dissolved with gentle heating and then allowed to stand for48 hours at room temperature. Subsequently, it is concentrated in vacuo.The residue obtained is a dark colored oil which solidifies by theaddition of petroleum ether. It is then sucked off, dried and trituratedseveral times with warm water.

Maximal change Maximal change in Maximal change of Preparation LD 50Dosage of the cerebral oxygen tension of the blood pressure gjkg.mg./kg. blood flow the brain'surface (systolic/diastolic) mouse in inmin. in in minutes in 70 in minutes 3-( 3'-methoxybenzoyl)-2- 1.0 5.0+153 +32/+5l l5 (a-methyl-B-hydroxy-phenp.o. i.v.

ethylamino)-propionitrile +142 180 0/0 3-(2,3,4' trimethoxy- 5.0 +228 30+47 3 +24l+25 l3 hydroxy-phenethylamino)- pro. 10.0 +173 +200 50 +38l+2618 propionitrile i.d.

benzoyD-Z-(a-methyl-B- i.v.

hydroxy-phenethylamino)- 1 v 10.0 +44 25 +75 16 3/14 7propionitrile-hydrochloride benzoyD-Lta-methyl-B- 5.0 +121 38 +34 14+18l+40 30 hydroxy-phenethylamino)- i.v.

propionitrile-hydrochloride (a-methyl-B-hydroxy-pheni.v.

ethylaminol-propionitrile 7.0 +133 18 0/0 hydrochloride i.d.

(u-methyl-:b-hydroxy-phen- 2.0 +205 19 +106 42 +l27/+|52elhylaminol-propionitrile- H i.v.

hydrochloride (a-methyl-B-hydroxy- 2.0 +90 14 1 1phenethylamlno)-propioi, l0 HS/+50 17 nitrile hydrochloridetrimethoxyphenethyl- +22/+2 8 amino)-propionitrilehydrochloridetn'methoxyanilino)-carbonylmethyl-piperazinyl- 1.0 10.0 30 +8 (1')]-propionitn'lep.o. i.d. 20 +2 n+5 20 dihydrochloriderazinyl(1')]-propionitriledihydrochloride comparative substance: 10.0 00 0 0 0 I 0 cinnarizine i.d.

The following examples are given for the purpose of a betterunderstanding of the nature and the objects of this invention. Thetemperatures are given in degrees Centigrade.

The water-insoluble part is separated, dried, recrystallized once frombenzene/petroleum ether and converted with ethanolic hydrochloric acidand with the 5 concurrent use of anhydrous ether to the hydrochloride.The hydrochloride is reconverted in the usual manner to the base. Afterrecrystallization from benzene/petroleum ether one obtains the3-(pchlorobenzoyl)-2-(a-methyl-B-hydroxy-phenethylamino)-propionitrilehaving a melting point of l 12-1 14.

calculated: C (16.6 H 56 found; 66.3 5 5 8 Yield: 2.) g. 56.571 of thetheoretical tone. The dry product is then suspended in 90 c.c. benzene,a solution consisting of 3.8 g. trimethylam monium chloride in 4 c.c.water is added and a further solution consisting of7 g. KCH in 36 c.c.water is added dropwise while cooling with ice and stirring. Thereaction mixture is then heated to room temperature, stirred for anotherhours, the benzene phase is separated and the aqueous phase is extractedtwice with benzene. The combined benzene phases are washed once withwater, dried with Na SO and concentrated inv vacuo. By recrystallizationof the muddy residue from ligroin one obtains the pchlorobenzoylacrylonitrile having a melting point of l44l46.

Analysis: (C H Cl N,O

calculated: C 62.6 H 3.1 N 7 found: 63.0 3.5 7. Yield: 7.9 g. 59.4% ofthe theoretical Analogously to the description given hereinbefore it ispossible to prepare, for instance, the following benzoylacrylonitriles:

Melting I point Boiling (degrees) point Gal [5 83-85 3-Cll3OCull4 J2 I oOCII=ClI-Cl Melting I point (degrees) Boiling point 0on5 94l2 mm.Z-Br-Calh 119123/2 mm. 3-NO2C6ll-I 74 4-(ll:|(Julli. 107111/2mm. 4(zlln-Culh 112118/1 mm. l-(/(tll17-'(/I'll4-- 178-l85/1.5 mm.

2,4,5-Cl3"-Callz EXAMPLE 2 3.09 g. 2-[piperazinyl(1)]-acetic acid-33435trimethoxyanilide are dissolved in 50 c.c. dioxane, 2.66 g.2,3,4-trimethoxybenzoylacrylic acid are added and the mixture is stirredfor 30 hours at The separated precipitate is sucked off, washed firstwith dioxane, then thoroughly with water, dried and finally boiled withc.c. alcohol. The residue thus obtained is the3-[2',3,4-trimethoxybenzoyl]-2-[4-(3,4,5-trimethoxyanilino)-oxoethyl-piperazinyl (l)]-propionic acid.

The same product is' obtained by treating N-[Z-(2',3,4-trimethoxybenzoyl)-l-cyanoethyl]-N'-(acet-3,4',5-trimethoxy-anilido)piperazine-hydrochloride (prepared by additionof Z-[piperazinyl (l)]-acetic acid-3',4',5-trimethoxyanilide on2',3,4-trimethoxybenzoylacrylonitrile analogously to the prescription ofExample 5, melting point: 181) with concentrated sulfuric acid. The acidmay be converted with an equimolar amount of sodium ethylate to itssodium salt.

Melting point: 250 dec.

The 2,3,4'-trimethoxybenzoylacrylic acid required as starting materialmay be prepared as follows:

4.5 g. 2,3,4-trimethoxybenzoyl-acrylic acid amide are dissolved withstirring in 34 c.c. concentrated sulfuric acid. The mixture is cooleddown to an internal temperature of45, 3.55 g. NaNO are added and then 10c.c. water are slowly added dropwise with stirring, whereby thetemperature rises to -l0. Subsequently, a further 51 c.c. water areadded dropwise in such a manner that finally the temperature reaches +3and stirring in continued for another minutes at room temperature. Thereaction mixture is then sucked off, the residue is washed with water,dissolved in soda solution of 10%, filtered off from a slightly turbidmass and the filtrate is acidified with hydrochloride acid of 10%.Obtained is an oily precipitate which solidifies after a short while.The reaction product is sucked off, washed with water and dried, thendissolved with gentle heating in toluene and filtered off from a minorresidue. The filtrate is admixed with petroleum ether and the separatedprecipitate is sucked off. Obtained is the 2',3',4'-trimethoxybenzoylacrylic acid.

Melting point: 89-90 Analysis: (C H Cl N Ofl Analysis: (CUHHOB)calculated: C 55.5 H 6.0 N 7.2 calculated: c 58.6 H 5.3 o 36.1 found:found: 5 3 5 Yield: 2.9 g. 53% of the theoretical Yield: 3.3 g. 73% ofthe theoretical The 3'-methoxybenzoylacrylonitrile required as The2-[piperazinyl (l)]-acetic aeid-3,4,5- starting material may be preparedanalogously to the trimethoxy-anilide which is also required as startingmaterial may be prepared as follows:

18.3 g of 3,4,5-trimethoxyaniline and 10.1 g. triethylamine aredissolved in 300 c.c. anhydrous dioxane, 1 1.3 g. chloroacetylchlorideare added at -20 with stirring and the reaction mixture is stirred for16 hours at room temperature. It is then sucked off from the separatedtriethylammonium chloride, the filtrate is evaporated in vacuo, theresidue is treated with ether and sucked off.

Obtained are 23 g. N-ch1oroacetyl-3',4,5'- trimethoxy-aniline having amelting point of 103.

A solution consisting of 27 g. piperazine in 100 c.c. isopropanol isadmixed, while stirring at room tempera,- ture, with a solutionconsisting of 14 g. N-chloroacetyl- 3',4,5-trimethoxyani1ine in 60 c.c.dioxane. The reaction solution is then heated for 7 hours under reflux,evaporated and the residue is dissolved in 2N sodium hydroxide solutionand chloroform. The chloroform phase is separated. the aqueous phase isagain extracted with CHCl both chloroform extracts are combined, washedand concentrated in vacuo. The remaining oil solidifies by the additionof diisopropylether. Obtained are after suction-filtration 15 g. 2-[piperazinyl (l)]-acetic acid-3,4,5'-trimethoxyanilide having a meltingpoint of 125.

EXAMPLE 3 2 g. 3'-methoxybenzoylacrylonitrile are dissolved in 30 c.c.dioxane, 1.39 g. N-hydroxyethylpiperazine are added and the solution isfirst allowed to stand for one hour at room temperature and thenconcentrated in vacuo. The residue is recrystallized frombenzene/petroleum ether. Obtained are 3.2 g. N-[2-(mmethoxybenzoyl)-lcyano-ethyll-N'-[hydroxyethy1]- piperazine having a melting point of126l28.

3.2 g. of the hydroxyethylpiperazine are dissolved in 40 c.c. dioxane,1.03 g. triethylamine are added and, at room temperature. a solutionconsisting of 2.33 g. 3,4,- S-trimethoxybenzoylehloride in 15 c.c.dioxane is added dropwise while stirring. Subsequently, the reactionmixture is stirred for another 16 hours at room temperature. A further0.54 g. triethylamine as well a solution consisting of 1.14 g.3.4,5-trimethoxybenzoylchloride in dioxane are added and this mixture isagain stirred for 16 hours at room temperature. After sucking off, thefiltrate is concentrated in vacuo, the residue is dissolved in ethanolichydrochloric acid and admixed with ether. The precipitate obtained is aslightly muddy hydrochloride. After conversion to the base andsubsequent reconversion to the hydrochloride one obtains theN-[2-(m-methoxybenzoyl-l-cyanoethyl]-N-[ 3,4,5-trimethoxybenzoyloxyethyl]- piperazine-dihydrochloride in the formof crystals melting at 146.

description given in Example 1 from 3'-methoxybenzoylvinylchloride. The3-methoxybenzoylvinylchloride required for this purpose may be preparedas follows:

A solution consisting of 17.8 g. ethyl formiate and 30 g.3-methoxyacetophenone is added dropwise, while stirring at 8-10, to asuspension of 13 g. sodium methylate in 100 c.c. anhydrous benzene.Stirring is continued for another 16 hours at room temeprature, then thereaction mixture is sucked off, washed with anhydrous alcohol and theresidue is dried in vacuo. Obtained are 38.9 g. of the sodium salt ofthe 3'-methoxybenzoylvinyl alcohol.

24.2 g. of the sodium salt are suspended in c.c. benzene. Subsequently,c.c. water and 60 c.c. sulfuric acid of 10% are added and the mixture isvigorously stirred. When it is completely dissolved, the benzene layeris separated and the aqueous phase is extracted twice with benzene.

The combined benzene extracts are then gently heated under reflux with15.4 g. thionylehloride, the excess thionyl chloride and the benzene arethen distilled off in vacuo and the residue is fractionated in vacuo.

Obtained is the 3'-methoxy-benzoylvinylehloride.

Boiling point: l50/3-4 mm. Analysis: (C H CIO calculated: C 61.0 H 4.5found: 60.7 4.5 Yield: 16.2 g. 38% of the theoretical Analogously, thefollowing methoxylated benzoylvinylchlorides may be prepared from thecorresponding acetophenones via the sodium salts of thebenzoylvinylalcohols:

added and the mixture is stirred for 20 hours at room temperature, thenheated during one hour at 80 and the solution is concentrated in vacuo.The remaining oil solidifies when it is treated with ether. The residueis sucked off. washed with ether. then dissolved in warmed ethyl acetateand the filtrate is admixed with 1 1 petroleum ether whereby aprecipitate is formed which crystallizes after a short while. It issucked off and the residue is washed with petroleum ether.

EXAMPLE 8.8 g. 3,4',5-trimethoxybenzoylacrylonitrile and I l g.2-[piperazinyl (l) -acetic acid-3 ,4',5

I I I O O n T Obtamed ,3 trimethoxyanilide are stirred for 7 hours at 70in 120 mmethoxlfbenzoyn'l'carbonamldo'ethyll 5 c.c. dioxane. Thesolution is then cooled down to room norephcdrmtemperature, filtered offfrom residual parts, if any, and the filtrate is evaporated in vacuo.The oily residue is dissolved in little anhydrous dioxane, admixed withMelting point: i05 etheric hydrochloric acid, and the precipitate issucked Arwlysisl (C'ZZHZKNZOH) off and washed several times with ether.Subsequently, culculmed: C 635 H 67 N 647 O 23.] it is treated withwater, whereby first muddy mass is found: 63.4 7.1 6.4 23.5 formed whichsolidifies while further standing. The 67% hememal solid product issucked off, suspended in dilute soda so lution and immediately extractedthree times with chloreform. The chloroform solution is washed withwater, The 4I trimethoxybenzoylacrylic acid amide dried and concentratedin vacuo. The resinous residue 9 i Q quired as Starting material may beprepared as follows. is dissolvedin anhydrous dioxane, admixed withetherc 8 g 2,,3i,4i trimethoxybenzoylacrylonitrne are hydrochloric acid andthe separated precipitate is solved in 40 c.c. concentrated sulfuricacid and heated sulcked Off and Washefj ether The resldue in a waterbath to an internal temperature of 75. At surred for one hollr m about30 CC waterfiwhereby this temperature, the mixture is allowed to standfor 3 first a mud'dy mass is agaln formed wh'ch sohqlfies after minutesthen Cooled and poured Onto about 120 g ice a short while. After suckingoff and recrystallizing from Q I I I I The precipitated residue issucked off and washed l ki b 1 T' h l N 'm-$3 twice with little icedwater. By recrystallization of the trlmethoxy 3 'f l y f 9 residue fromwater and with the concurrent use oflittle mmet oxyamh0)-plperazme'hydrochlonde' methanol one obtains the2',3,4-trimethoxybenzoylacrylic acid amide.

Melting point: 178 Analysis: (CMHMCMNJOX) calculated: C 56.7 H 6.2 CI6.0 N 9.4 found: 56.8 6.4 5.8 9.6 Melting point: ll52 Analysis:(C1;,H,,,NO5)

niculineti: 5x1: H 5.7 N 5.3 35 Analogously to the description given inExamples l gl l f s g 7M Tihcmctiil 5 the following compounds of thepresent invention may be obtained:

I -C()Cll2(]jll-lt:

I I Melting R: {)Oil'li, (degrees) 2,3,4-(CIIiOhCaH: CN 30m -NNo2H40-oo--oc11i 2,3,4-(CH30)3C6H2 o ONHQ (ion: 18?

Q -N N"C21I40' C 0 00113 CH-B 2,3,4-(CH30)3C6H2 CN 107 NCH2CH 4-cinocnnCOOII ooiii 221 N N mil-in u (to mini 1 Hull 3-(,Jllu()-(.-nll5 (.N n2

- I()ll (!l'lcm on i Y 3 )-3 flI 2 CN 108 2 Hydrochloride. D291. ,s Whatwe claim is: l. A compound of the formula wherein Z stands for a memberselected from the group consisting of OH. NH; and ONa, X stands foralkylene with l 4 carbon atoms, Y stands for a member selected from thegroup consisting of OCO and CO-NH. the nucleus 1 being selected from thegroup consisting of phenyl and mono-, diand trimethoxyphenyl. andnucleus ll being selected from the group consisting of phenyl and mono-,diand trimethoxyphenyl, and the pharmaceutically acceptable acidaddition salts of said compounds.

2. Compound according to claim 1, wherein nucleus I ismonomethoxyphenyl, Z is OH, X is C H Y is OCO- and nucleus ll istrimethoxyphenyl, and

Y is -OCO, nucleus ll is trimethoxyphenyl, and the pharmaceuticallyacceptable addition salts of said compound.

5. Compound according to claim 1, wherein nucleus 1 is trimethoxyphenyl,Z is -OH, X is --CH Y is CONH, nucleus [1 is trimethoxyphenyl, and thepharmaceutically acceptable addition salts of said compound.

1. A COMPOUND OF THE FORMULA
 2. Compound according to claim 1, whereinnucleus I is monomethoxyphenyl, Z is -OH, X is -C3H6-, Y is -O-CO- andnucleus II is trimethoxyphenyl, and the pharmaceutically acceptableaddition salts of said compound.
 3. Compound according to claim 1,wherein nucleus I is trimethoxyphenyl, Z is -NH2, X is -C2H4-, Y is-O-CO-, nucleus II is trimethoxyphenyl, and the pharmaceuticallyacceptable addition salts of said compound.
 4. Compound according toclaim 1, wherein in nucleus I is trimethoxyphenyl, Z is -ONa, X is-C3H6-, Y is -O-CO-, nucleus II is trimethoxyphenyl, and thepharmaceutically acceptable addition salts of said compound.
 5. Compoundaccording to claim 1, wherein nucleus I is trimethoxyphenyl, Z is -OH, Xis -CH2-, Y is -CO-NH-, nucleus II is trimethoxyphenyl, and thepharmaceutically acceptable addition salts of said compound.